The synthetic and biological study of bryostatin analogues

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Title The synthetic and biological study of bryostatin analogues
Publication Type dissertation
School or College College of Science
Department Chemistry
Author Li, Wei
Date 2011-05
Description Bryostatins is a novel family of marine natural products that were originally isolated by Pettit from the bryozoan Bugula neritina. Since its isolation, bryostatin 1 has gained extensive attention due to its unique biological activities. It has been shown to restore the apoptosis of cancer cells, reverse the multidrug resistance, stimulate the immune, synergize with other antineoplastic agents. Bryostatin 1 also demonstrates its capabilities of promotion of memory, recovery from the stroke and treatment of Alzheimer's Disease. All those unique bioactivity are possibly related to the interaction with protein kinase C isozymes (PKC). Bryostatin 1 has been proved to be able to activate PKC through the binding with C1 domain of PKC, which initiates a variety of downregulation responses to the proliferation, division and apoptosis of cell. Bryostatin 1 is not the only ligand binding with PKC C1 domain. In comparison with other PKC activator such as phorbol esters, bryostatin 1 is nontumor promoting, can even antagonize the tumor promoting effect of phorbol ester, which makes it in the front line for the development of new drug lead that target PKC. The research on bryostatin has been hampered by its limited supply due to the low abundance in nature source. Our group has been involved in the synthesis of bryostatin and analogues to solve the problem of supply of bryostatin. Described herein is the exploration of convergent and efficient routes to prepare bryostatin analogues. Pyran annulation has been proven to be versatile and tolerant of functional groups in construction of 2,6-syn pyran. Its application in our analogue synthesis successfully delivered the target molecules, which demonstrated high binding affinity with PKC, but the biological result of bryostatin analogue with C7 acetate indicated it behaved like phorbol ester instead of bryostatin 1. In order to understand the role of northern hemisphere of bryostatin on its biological activities, analogue with functional group on different positions in the northern region is investigated systematically. The biological results from these analogues will help us to clarify the pharmacophoric groups that define the unique biological activities of bryostatin 1.
Type Text
Publisher University of Utah
Subject Bryostatin analogues; Bryostatins; Organic synthesis; Protein kinase C; Pyran annulation; Marine pharmacology; Bugula neritina
Dissertation Institution University of Utah
Dissertation Name Doctor of Philosophy
Language eng
Rights Management Copyright © Wei Li 2011
Format application/pdf
Format Medium application/pdf
Format Extent 24,851,722 bytes
Identifier us-etd3,25429
Source Original housed in Marriott Library Special Collections, RS43.5 2011 .L5
ARK ark:/87278/s6k07k2c
Setname ir_etd
ID 194784
Reference URL https://collections.lib.utah.edu/ark:/87278/s6k07k2c
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